US4301163A - Amino-ether oxides and use thereof in therapy - Google Patents

Amino-ether oxides and use thereof in therapy Download PDF

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US4301163A
US4301163A US06/164,931 US16493180A US4301163A US 4301163 A US4301163 A US 4301163A US 16493180 A US16493180 A US 16493180A US 4301163 A US4301163 A US 4301163A
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phenyl
amino
lower alkyl
equal
ether
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Dieran R. Torossian
Claude P. Roux
Gilbert G. Aubard
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Industrielle de Produits de Synthese Ste
Jouveinal SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5

Definitions

  • the present invention relates to novel amino-ether oxides, a process for the preparation thereof and use thereof in human and veterinary medicine.
  • amino-ether oxides according to the invention conform to the formula: ##STR2## in which:
  • R 1 is a lower alkyl
  • R 2 and R 3 which are the same or different are hydrogen or lower alkyl
  • R 4 is a phenyl or phenoxy nucleus optionally monosubstituted to trisubstituted by substituents which are identical or different, halogen or lower alkoxy,
  • R 5 is a phenyl radical optionally monosubstituted to trisubstituted by substituents which are the same or different, halogen, lower alkyl, lower alkoxy or nitro, a pyridyl radical or a lower alkyl radical,
  • n is equal to zero, 1 or 2
  • n and q are, independently of one another, equal to zero or to 1,
  • p is an integer ranging from 0 to 9.
  • lower radical are meant radicals having from 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, especially 1 to 4 carbon atoms in a straight or branched chain.
  • R 5 is alkyl, it is preferably methyl. If the amino-ether oxides are halogenated, they are preferably brominated or chlorinated.
  • the invention also embraces the acid addition salts of amino-ether oxides, notably those of mineral acids, such as halohydrates, sulphates, phosphates, or organic acids such as maleates, citrates, malates, tartrates, methanesulphonates, camphosulphonates, benzoates, etc.
  • the invention covers both racemic and optionally active forms which can be separated, particularly by forming salts with optically active acids.
  • a compound of formula AX can be condensed with an alcoholate of formula BOM, one of A and B being the radical ##STR3## when the other is the radical R 5 --(CH 2 ) p --, X being an anionic radical and M being an alkali metal, the acid addition salts being obtained conventionally by salification by means of the selected acid.
  • X preferably represents bromine or chlorine, but it can also be an anionic sulphate, benzosulphonate, methanesulphonate or p-toluenesulphonate radical.
  • the alcoholates in which the radicals R 1 to R 4 appear can be prepared by reacting an alkali metal M, especially sodium or potassium or their hydrides or amides, with the corresponding amino-alcohols prepared as described in French Pat. Nos. 912,577 or 71.08700 or according to the method described by Chapman and Triggle in "J. Chem. Soc.” 1963, page 4835.
  • an alkali metal M especially sodium or potassium or their hydrides or amides
  • the reaction is effected in aromatic solvents such as benzene, toluene, xylenes or in ether solvents such as diethyl ether, dioxane, tetrahydrofuran or aprotic solvents such as dimethyl sulphoxide, dimethyl formamide (DMF), acetonitrile, dimethyl acetamide, hexamethyl phosphorotriamide (HMPT); this last group of solvents is especially preferred when the salification agent is in the form of the hydride or amide of the alkali metal M.
  • aromatic solvents such as benzene, toluene, xylenes or in ether solvents such as diethyl ether, dioxane, tetrahydrofuran or aprotic solvents
  • DMF dimethyl formamide
  • HMPT hexamethyl phosphorotriamide
  • the reaction is effected at a temperature of between 0° and 140° C., especially between 20° and 110° C.
  • the reaction time varies according to the reagents and the temperature and is between 15 minutes and 24 hours, especially between 30 minutes and 6 hours.
  • the reactive esters and particularly the halides in which the radical R 5 appears are prepared according to the method of Shepard and Noth described in the "Journal of the American Chemical Society” 1950, page 4364, in which alcohol is reacted with thionyl chloride, or according to the method of Ctvrtnik described in "Chemical Abstracts” 1956, Vol. 50 10130 c, by chloromethylation of aromatic nuclei.
  • the halides and others in which the radicals R 1 to R 4 appear are prepared, for example, according to the method described in "Organic Syntheses" Coll. Vol. IV, page 333, or by the numerous other methods referred to in this article.
  • the condensation of AX and of BOM is effected at a temperature of between 0° and 140° C., preferably between 70° and 110° C.
  • the reaction time is between 1 and 24 hours, preferably between 4 and 12 hours.
  • the progress of the reaction can be followed by thin-layer chromatography.
  • the amino-ether oxide is separated from the reaction medium by methods well known to a person skilled in the art, such as, for example, extraction, precipitation, fractional distillation, crystallisation of salts, etc.
  • R 1 ethyl
  • R 4 phenyl
  • R 5 ,4-dimethoxyphenyl
  • the mixture is refluxed with vigorous stirring to disperse the sodium.
  • the suspension is filtered and the solvent of the filtrate is eliminated by distillation in vacuo.
  • the residue is taken up with 2 liters of hydrochloric acid (2N) and extracted with diethyl ether.
  • the ether phases are removed and the aqueous acid phase is made alkaline in the cold with sodium hydroxide solution (10N) in a quantity sufficient to obtain a pH value of 12.
  • the oil formed is extracted with ether, the ether phases are washed with water and then dried over sodium sulphate and the ether is eliminated by distillation.
  • the oily residue obtained is purified by fractionation in vacuo.
  • the DL camphosulphonate of the product is prepared in ethanol and recrystallised in ethyl acetate.
  • R 1 ethyl
  • R 4 phenyl
  • R 5 3,4,5-trimethoxyphenyl
  • the mixture is subsequently maintained for 5 hours at 70° to 75° C. and is then cooled to 20° c.
  • the suspension obtained is introduced into 250 liters of iced water and is then acidified with concentrated hydrochloric acid until a pH value of 1 is obtained.
  • the mixture is extracted with toluene.
  • the toluene phases are removed and the aqueous acid phase is made alkaline until a pH value of 12 is obtained with a sodium hydroxide solution (10N) and the mixture is extracted with methylene chloride.
  • the methylene chloride phases are washed with water, dried over Na 2 SO 4 and the methylene chloride is eliminated by distillation.
  • the residue is solubilised in 200 liters of hexane at boiling point, filtered hot and the filtrate cooled with stirring.
  • the product is filtered, washed with cold hexane and dried in vacuo at ambient temperature.
  • the hemi-maleate of the product is prepared and recrystallised in water.
  • R 1 ethyl
  • HMPT hexamethyl phosphorotriamide
  • the suspension is then maintained with stirring for 5 hours at 70° to 75° C. and is then left overnight at ambient temperature.
  • the reaction medium is precipitated in 1 liter of iced water and the mixture is acidified with hydrochloric acid in a quantity sufficient to obtain a pH value of 1 and is extracted with diethyl ether.
  • the ether phases are eliminated and the aqueous acid phase is made alkaline by a sodium hydroxide solution until a pH value of 12 is obtained.
  • the suspension is extracted with diethyl ether, the combined ether phases are washed with water and dried over anhydrous sodium sulphate and the ether is then eliminated by distillation.
  • the residue is purified by fractional distillation in vacuo.
  • the maleate of the product is prepared in ethanol and recrystallised in water.
  • the amino-ether oxides listed in table 1 below are obtained from 2-phenyl-2-dimethylamino-1-butanol and halides of formula R 5 --(CH 2 ) p X.
  • R 1 ethyl
  • R 4 phenyl
  • R 5 3,4,5-trimethoxyphenyl
  • R 1 ethyl
  • R 2 H
  • R 3 methyl
  • R 4 phenyl
  • R 5 trimethoxyphenyl
  • R 4 (4-chloro)phenoxy
  • R 5 2-methoxy-5-nitrophenyl
  • R 1 ethyl
  • R 4 phenyl
  • R 5 4-methoxyphenyl
  • R 1 ethyl
  • R 4 phenyl
  • R 5 4-methoxyphenyl
  • the ether phase is separated and the aqueous phase is re-extracted twice with ether.
  • the combined ether phases are washed with water and then dried over Na 2 SO 4 .
  • the ether is eliminated at 20° C. by distillation in vacuo.
  • HMPT hexamethylphosphorotriamide
  • reaction mixture is subsequently heated for 4 hours to 70° C. and left to stand overnight.
  • amino-ether oxides according to the invention possess local and spasmolytic anesthetic properties. Certain products also have a considerable analgesic activity. These various properties make the products according to the invention valuable pharmaceutical agents.
  • the acute toxicity of the products of the invention was determined on groups of 20 Swiss OF1 mice weighing 22 to 24 grams by intravenous route. These toxicities are expressed as the LD 50 corresponding to the dose at which a 50% mortality of the treated animals is noted after 8 days of observation. The limits of confidence of these values were determined by the method of Litchfield and Wilcoxon (J. Pharmacol. Exp. Ther. 1949, pages 96 to 99) and are given in table III.
  • the local anaesthetic activity on contact is determined on the cornea of the rabbit according to a method derived from the technique of Regnier (Regnier J. R. Salle P. Bull. Soc. Pharmacol. 1926 33, 91).
  • mice Male albino rabbits weighing 2 to 3 kg are used in groups of 5.
  • the product solution to be tested is injected in a volume of 0.2 ml into the conjunctival sac.
  • the cornea is then stimulated by means of a hair 3, 6, 10, 15, 20, 25, 45 and 60 minutes after injection.
  • the average number of stimulations is calculated for each group and this number is compared with that obtained with a lidocaine hydrochloride solution of equal concentration.
  • the local anaesthetic activity is thus expressed in relation to this reference product.
  • the organ fragments were kept alive in a tank containing a solution of Tyrode (37° C., pH 7.2, oxygenated by the mixture O 2 /CO 2 , 95%/5%).
  • the isotonic contractions were recorded graphically on a physiograph by means of a transducer.
  • the effect-dose straight line is determined according to semi-logarithmic coordinates and the EC 50 is calculated graphically, that is the concentration of the substance necessary to reduce by 50% the amplitude of the contraction of convulsant agent.
  • the values obtained are compared with those of spasmolytic agents selected as reference and are determined under the same experimental conditions, namely:
  • the analgesic activity of the products was studied on male Sprague-Dawley rats in groups of 15 by a method derived from that of Randall and Selito (Arch. Int. Pharmacodyn. 1957 (III) page 409).
  • This method consists in causing a painful inflammation in the paw of the rat by injecting 0.1 ml of a 20% brewer's yeast solution, then applying a pressure to the inflammation and determining the value of the pressure at which a painful reaction of the animal appears.
  • the activity of the products was studied after 1 hour of administration by oral route at the rate of one dose of 100 mg/kg in comparison with untreated animals.
  • aspirin was chosen as reference substance.
  • the analgesic effect of the products is expressed by the percentage increase of the pressure endured by the treated animals in relation to that endured by the untreated animals.
  • results of the analgesic activity of the product tested are expressed in relation to the activity of aspirin administered by oral route at a dose of 100 mg/kg.
  • results obtained are collated in table VI.
  • the compounds of the invention show anti-spasmodic, anaesthetic and analgesic activities useful in therapy.
  • gastroenterology in oesophagitis, gastroduodenal ulcer, gastritis, biliary dyskinesia, hepatic colic, spasmodic colitis, gastrointestinal malfunction as well as for the treatment of nausea and vomiting;
  • the unit therapeutic dose of the products is between 10 and 200 mg, preferably between 20 and 100 mg of active ingredient for 100 to 2000 mg of excipient.
  • the daily therapeutic dose is between 10 mg and 2 grams, preferably between 50 and 500 mg.
  • the active ingredients of the present invention are administered by the various routes applicable to humans and in the therapeutic forms compatible with these routes.
  • gelatine and medicinal white sugar are dissolved separately in water.
  • the two solutions are mixed and the polyethylene glycol 6000 is added thereto.
  • lactose and mannitol are mixed intimately and then the active substance of Example 2, corn starch and the solution obtained above are added in order.
  • the paste is dried, granulated and screened, while adding the magnesium stearate and corn starch.
  • the obtained product is homogenised and compressed at the rate of 200.0 mg per tablet.
  • the isotonic solution is distributed in ampoules of suitable volume which, after sealing, are sterilised by thermal means known per se or the solution is sterilised by filtration and distributed in ampoules which are then sealed. All these operations are effected under sterile atmosphere.
  • the LD 50 of papaverine hydrochloride and of hexamethonium bromide are respectively 33.1 and 21.0 mg/kg.
  • the other compounds of the invention show a comparable local activity.
  • the other compounds according to the invention have comparable spasmolytic properties.
  • This index I was calculated with regard to both the activity and the relative toxicity of the products of the invention in relation to the reference substances, namely lidocain hydrochloride, papaverine hydrochloride and hexamethonium dibromide. To eliminate the differences due to the molecular weights of the products, the calculations were made in mmoles. ##EQU1##
  • the relative index of activity of the products of the invention in local anaesthesia is at least comparable to that of lidocaine hydrochloride and is in many cases 1.5 to 3 times higher.
  • the spasmolytic activity in vitro as compared with papaverine shows that, apart from the products of Examples 5, 9 and 10, the indices are up to seven times higher than those of the reference for the products of Examples 2 and 21.

Abstract

Amino-ether oxides of formula: ##STR1## in which R1 is lower alkyl, R2 and R3 which are the same or different are hydrogen or lower alkyl, R4 is a phenyl or phenoxy nucleus optionally monosubstituted to trisubstituted by substituents which are the same or different, halogen or lower alkoxy, R5 is a phenyl radical optionally monosubstituted to trisubstituted by substituents which are the same or different, halogen, lower alkyl, lower alkoxy or nitro, a pyridyl radical or a lower alkyl radical, n is equal to zero, 1 or 2 and p is an integer from 0 to 9, m and q are equal to zero or 1.
Local and spasmolytic anaesthetics.

Description

The present invention relates to novel amino-ether oxides, a process for the preparation thereof and use thereof in human and veterinary medicine.
The amino-ether oxides according to the invention conform to the formula: ##STR2## in which:
R1 is a lower alkyl,
R2 and R3 which are the same or different are hydrogen or lower alkyl,
R4 is a phenyl or phenoxy nucleus optionally monosubstituted to trisubstituted by substituents which are identical or different, halogen or lower alkoxy,
R5 is a phenyl radical optionally monosubstituted to trisubstituted by substituents which are the same or different, halogen, lower alkyl, lower alkoxy or nitro, a pyridyl radical or a lower alkyl radical,
n is equal to zero, 1 or 2,
m and q are, independently of one another, equal to zero or to 1,
p is an integer ranging from 0 to 9.
By lower radical are meant radicals having from 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, especially 1 to 4 carbon atoms in a straight or branched chain.
If R5 is alkyl, it is preferably methyl. If the amino-ether oxides are halogenated, they are preferably brominated or chlorinated.
The invention also embraces the acid addition salts of amino-ether oxides, notably those of mineral acids, such as halohydrates, sulphates, phosphates, or organic acids such as maleates, citrates, malates, tartrates, methanesulphonates, camphosulphonates, benzoates, etc.
The invention covers both racemic and optionally active forms which can be separated, particularly by forming salts with optically active acids.
To prepare the amino-ether oxides according to the invention, a compound of formula AX can be condensed with an alcoholate of formula BOM, one of A and B being the radical ##STR3## when the other is the radical R5 --(CH2)p --, X being an anionic radical and M being an alkali metal, the acid addition salts being obtained conventionally by salification by means of the selected acid.
X preferably represents bromine or chlorine, but it can also be an anionic sulphate, benzosulphonate, methanesulphonate or p-toluenesulphonate radical.
The alcoholates in which the radicals R1 to R4 appear can be prepared by reacting an alkali metal M, especially sodium or potassium or their hydrides or amides, with the corresponding amino-alcohols prepared as described in French Pat. Nos. 912,577 or 71.08700 or according to the method described by Chapman and Triggle in "J. Chem. Soc." 1963, page 4835. The reaction is effected in aromatic solvents such as benzene, toluene, xylenes or in ether solvents such as diethyl ether, dioxane, tetrahydrofuran or aprotic solvents such as dimethyl sulphoxide, dimethyl formamide (DMF), acetonitrile, dimethyl acetamide, hexamethyl phosphorotriamide (HMPT); this last group of solvents is especially preferred when the salification agent is in the form of the hydride or amide of the alkali metal M.
The reaction is effected at a temperature of between 0° and 140° C., especially between 20° and 110° C.
The reaction time varies according to the reagents and the temperature and is between 15 minutes and 24 hours, especially between 30 minutes and 6 hours.
The reactive esters and particularly the halides in which the radical R5 appears are prepared according to the method of Shepard and Noth described in the "Journal of the American Chemical Society" 1950, page 4364, in which alcohol is reacted with thionyl chloride, or according to the method of Ctvrtnik described in "Chemical Abstracts" 1956, Vol. 50 10130 c, by chloromethylation of aromatic nuclei. The halides and others in which the radicals R1 to R4 appear are prepared, for example, according to the method described in "Organic Syntheses" Coll. Vol. IV, page 333, or by the numerous other methods referred to in this article.
These latter methods generally make it possible to obtain a product which can be used in the following condensation reaction:
either as such by releasing in situ the reactive ester from its salt by the action of a strong base such as an amine, for example triethylamine, or any other product which can effect this displacement;
or by displacing in a previous stage the amino-alcohol ester from its salt by the action of a suitable alkaline agent such as sodium hydroxide, extraction of the liberated product by means of an organic solvent such as, for example, diethyl ether or chloroform, then evaporation of this extraction solvent which leads to the reactive amino-alcohol ester which is used as such or in solution in the solvent suitable for the following condensation reaction.
The condensation of AX and of BOM is effected at a temperature of between 0° and 140° C., preferably between 70° and 110° C. The reaction time is between 1 and 24 hours, preferably between 4 and 12 hours. The progress of the reaction can be followed by thin-layer chromatography.
The amino-ether oxide is separated from the reaction medium by methods well known to a person skilled in the art, such as, for example, extraction, precipitation, fractional distillation, crystallisation of salts, etc.
The following Examples illustrate the invention.
EXAMPLE 1 (preferred) 1-[(3,4-dimethoxy)benzyloxymethyl]-1-phenyl-N,N-dimethyl-n-propylamine
R1 =ethyl, R2 =R3 =methyl, R4 =phenyl, R5 =,4-dimethoxyphenyl, n=q=0, m=p=1.
39.3 grams of sodium (1.71 mol) are introduced into 300 grams of 2-phenyl-2-dimethylamino-1-butanol (1.55 mol) in solution in 3 liters of anhydrous dioxane.
The mixture is refluxed with vigorous stirring to disperse the sodium.
After 6 hours 434 grams of 3,4-dimethoxy-α-chlorotoluene (2.34 mol) in solution in 1 liter of anhydrous dioxane are introduced within 30 minutes; the mixture is maintained for 6 hours at the reflux temperature of the solvent.
The suspension is filtered and the solvent of the filtrate is eliminated by distillation in vacuo.
The residue is taken up with 2 liters of hydrochloric acid (2N) and extracted with diethyl ether. The ether phases are removed and the aqueous acid phase is made alkaline in the cold with sodium hydroxide solution (10N) in a quantity sufficient to obtain a pH value of 12.
The oil formed is extracted with ether, the ether phases are washed with water and then dried over sodium sulphate and the ether is eliminated by distillation.
The oily residue obtained is purified by fractionation in vacuo.
B.p.0.2/0.5 =187°-193° C., weight: 271 grams, yield≃50%.
The DL camphosulphonate of the product is prepared in ethanol and recrystallised in ethyl acetate.
Yield=85%, M.p.=108° C.
EXAMPLE 2 (preferred) 1-[(3,4,5-trimethoxy)benzyloxymethyl]-1-phenyl-N,N-dimethyl-n-propylamine
R1 =ethyl, R2 =R3 =methyl, R4 =phenyl, R5 =3,4,5-trimethoxyphenyl, n=q=0, m=p=1.
2.07 kg of oily suspension of sodium hydride at 60% (51.75 mol) in 11.6 liters of anhydrous dimethylformamide (DMF) are introduced into a suitable reactor.
With stirring and maintaining the reaction temperature below 40° C. about 10.00 kg of 2-phenyl-2-dimethylamino-1-butanol (51.70 mol) in solution in 8.7 liters of anhydrous DMF are introduced within 45 minutes.
After introduction the suspension is maintained for 45 minutes at about 40° C. 11.20 kg (51.70 mol) of 3,4,5-trimethoxy-α-chlorotoluene in solution in 8.7 liters of anhydrous DMF are subsequently introduced within about 35 minutes and without exceeding 60° C.
The mixture is subsequently maintained for 5 hours at 70° to 75° C. and is then cooled to 20° c.
The suspension obtained is introduced into 250 liters of iced water and is then acidified with concentrated hydrochloric acid until a pH value of 1 is obtained.
The mixture is extracted with toluene. The toluene phases are removed and the aqueous acid phase is made alkaline until a pH value of 12 is obtained with a sodium hydroxide solution (10N) and the mixture is extracted with methylene chloride. The methylene chloride phases are washed with water, dried over Na2 SO4 and the methylene chloride is eliminated by distillation.
The residue is solubilised in 200 liters of hexane at boiling point, filtered hot and the filtrate cooled with stirring.
After the start of crystallisation the suspension is left overnight at 10° C.
The product is filtered, washed with cold hexane and dried in vacuo at ambient temperature.
Weight=12.2 kg, yield=63%, M.p.=55°-56° c.
The hemi-maleate of the product is prepared and recrystallised in water.
Yield=90%, M.p.=123°-124° C.
EXAMPLE 3 (preferred) 1-Benzyloxymethyl-1-phenyl-N,N-dimethyl-n-propylamine
R1 =ethyl, R2 =R3 =methyl, R4 =R5 =phenyl, n=q=0, m=p=1.
4.0 grams of sodium hydride at 90% (0.15 mol) are introduced into 30.0 ml of hexamethyl phosphorotriamide (HMPT).
A solution of 29.0 grams (0.15 mol) of 2-phenyl-2-dimethylamino-1-butanol in 30 ml of HMPT is introduced with stirring over about 30 minutes and without exceeding 30° C.
Stirring is maintained for 30 minutes after introduction and 19.0 grams of α-chlorotoluene (0.15 mol) in solution in 30 ml of HMPT are then added over 30 minutes at a temperature below 40° C.
The suspension is then maintained with stirring for 5 hours at 70° to 75° C. and is then left overnight at ambient temperature.
The reaction medium is precipitated in 1 liter of iced water and the mixture is acidified with hydrochloric acid in a quantity sufficient to obtain a pH value of 1 and is extracted with diethyl ether. The ether phases are eliminated and the aqueous acid phase is made alkaline by a sodium hydroxide solution until a pH value of 12 is obtained.
The suspension is extracted with diethyl ether, the combined ether phases are washed with water and dried over anhydrous sodium sulphate and the ether is then eliminated by distillation.
The residue is purified by fractional distillation in vacuo.
B.p.0.25 =157°-158° C., weight=21 grams, yield=49.4%.
The maleate of the product is prepared in ethanol and recrystallised in water.
Yield=95%, m.p.=113°-114° C.
According to the process described in Example 3, the amino-ether oxides listed in table 1 below are obtained from 2-phenyl-2-dimethylamino-1-butanol and halides of formula R5 --(CH2)p X.
              TABLE 1                                                     
______________________________________                                    
 Ex-                                                                      
ample                                                                     
No    p     X     R.sub.5   YIELD  Characteristics                        
______________________________________                                    
4     3     Br    CH.sub.3  30%    Bp.sub.1.2 = 118-119° C.        
5     9     Br    CH.sub.3  18%    Bp.sub.0.1 = 170-175° C.        
6     1     Cl                                                            
                   ##STR4## 72%    Bp.sub.0.6 = 161-172° C.        
7     0     Cl                                                            
                   ##STR5## 46%    Bp.sub.0.6 = 135-140° C.        
8     0     Cl                                                            
                   ##STR6## 53%    Bp.sub.0.5 = 150-152° C.        
9     1     Cl                                                            
                   ##STR7## 66%    Bp.sub.0.6 = 135-145° C.        
10    1     Cl                                                            
                   ##STR8## 52%    Bp.sub.0.8 = 162-163° C.        
______________________________________
EXAMPLE 11 2-[(3,4,5-trimethoxy)benzyloxy]-2-phenyl-N,N-dimethyl-n-butylamine
R1 =ethyl, R2 =R3 =methyl, R4 =phenyl, R5 =3,4,5-trimethoxyphenyl, n=m=0, p=q=1.
Prepared according to the process described in Example 3 from 1-phenyl-1-dimethylaminomethyl-1-propanol and from 3,4,5-trimethoxy-α-chlorotoluene.
Yield=70.5%, m.p.=84°-85° C.
Hydrochloride m.p.=208°-209° C.
EXAMPLE 12 (preferred) 1-[(3,4,5-trimethoxy)benzyloxymethyl]-1-phenyl-N-methyl-n-propylamine
R1 =ethyl, R2 =H, R3 =methyl, R4 =phenyl, R5 =trimethoxyphenyl, n=q=0, m=p=1.
Prepared by the process of Example 3 from 2-phenyl-2-methylamino-1-butanol and from 3,4,5-trimethoxy-α-chlorotoluene; the product is obtained in the form of a colourless and viscous oil which is analytically pure and appropriate.
Yield=60%, nD 20 =1.5491.
The corresponding amino-ether oxides and/or their salts listed in table 2 are obtained according to the process described in Example 3 and from amino-alcohols of structure ##STR9## and from halides R5 --(CH2)P --X.
                                  TABLE 2                                 
__________________________________________________________________________
Structures                                                                
 ##STR10##                                                                
Example                                                                   
No   R.sub.1                                                              
        p X R.sub.5 Z   Y   T   Yield                                     
                                    Characteristics                       
__________________________________________________________________________
13 Preferred compound                                                     
     CH.sub.3                                                             
        1 Cl                                                              
             ##STR11##                                                    
                    H   OCH.sub.3                                         
                            H   35% Maleate Mp = 102-105° C.       
14   CH.sub.3                                                             
        1 Cl                                                              
             ##STR12##                                                    
                    OCH.sub.3                                             
                        OCH.sub.3                                         
                            OCH.sub.3                                     
                                80% DL camphosulphonate Mp = 80°   
                                    C.                                    
15   CH.sub.3                                                             
        1 Cl                                                              
             ##STR13##                                                    
                    Cl  Cl  H   70% DL camphosulphonate Mp = 154°  
                                    C.                                    
16   C.sub.2 H.sub. 5                                                     
        1 Cl                                                              
             ##STR14##                                                    
                    OCH.sub.3                                             
                        OCH.sub.3                                         
                            H   33% DL camphosulphonate Mp = 120°  
                                    C.                                    
__________________________________________________________________________
EXAMPLE 17 1-Benzyloxymethyl-1-methyl-(3,4-dimethoxy)-phenethyl-amine
R1 =methyl, R2 =R3 =H, R4 =3,4-dimethoxyphenyl, R5 =phenyl, m=n=p=1, q=0.
Using the process described in Example 3 and starting from 2-[(3,4-dimethoxy)benzyl]-2-amino-1-propanol and from benzyl chloride the product is obtained which is crystallised in hexane.
Yield=47%, m.p. 97°-101° C.
According to the process described in Example 3 with amino-alcohols of structure ##STR15## R1 =R2 =R3 =methyl, R4 =3,4-dimethoxyphenyl, q=0, m=1, and the halides R5 --(CH2)p --X, the following amino-ether oxides are obtained.
______________________________________                                    
Ex-                                                                       
ample                                                                     
No    n     X     p   R.sub.5    Yield Characteristics                    
______________________________________                                    
18    1     Cl    1                                                       
                       ##STR16## 62%   Maleate Mp = 155-157° C.    
19    2     Cl    1                                                       
                       ##STR17## 47%   Base n.sub.D.sup.20                
______________________________________                                    
                                       = 1.5405
EXAMPLE 20 1-[(2-methoxy-5-nitro)benzyloxymethyl]-1-[(4-chloro)phenoxymethyl]-N,N-dimethylethylamine
R1 =R2 =R3 =methyl, R4 =(4-chloro)phenoxy, R5 =2-methoxy-5-nitrophenyl, n=m=p=1, q=0.
Prepared according to the process of Example 3, starting from 3-[(4-chloro)phenoxy]-2-dimethylamino-2-methyl-1-propanol and from 2-methoxy-5-nitro-α-chlorotoluene.
Yield=10%, nD 20 =1.5585.
EXAMPLES 21 AND 22 21: 1-[(4-methoxy)phenoxymethyl]-1-phenyl-N,N-dimethyl-n-propylamine.
R1 =ethyl, R2 =R3 =methyl, R4 =phenyl, R5 =4-methoxyphenyl, n=p=q=0, m=1.
22: 2-[(4-methoxy)phenoxy]-2-phenyl-N,N-dimethyl-n-butylamine.
R1 =ethyl, R2 =R3 =methyl, R4 =phenyl, R5 =4-methoxyphenyl, m=n=p=0, q=1.
100.0 grams of 4-methoxyphenol (0.80 mol) are dissolved in 1 liter of methanol. 250 ml of a methanolic solution of sodium methylate (0.80 mol) are then added with stirring and stirring is continued for 1 hour 30 minutes, the methanol then being eliminated by distillation in vacuo on a water bath at 60° C.; 117 grams of a beige yellow product are obtained which are used directly in the condensation reaction.
100 grams (0.40 mol) of 2-phenyl-2-dimethylamino-1-chlorobutane hydrochloride (m.p.=145°-147° C.) are dissolved in 500 ml of iced water. 500 ml of diethyl ether are added and the mixture is made alkaline when cold by a concentrated sodium hydroxide solution until a pH value of 12 is obtained.
The ether phase is separated and the aqueous phase is re-extracted twice with ether. The combined ether phases are washed with water and then dried over Na2 SO4. The ether is eliminated at 20° C. by distillation in vacuo.
A slightly viscous, colourless to light-yellow liquid is obtained.
Weight=82.2 grams, yield=96%.
In a suitable reactor 39.4 grams (0.27 mol) of sodium 4-methoxy-phenolate are dissolved in 125 ml of hexamethylphosphorotriamide (HMPT).
57 grams (0.27 mol) of 2-phenyl-2-dimethylaminochlorobutane in solution in 57 ml of HMPT are added with stirring over 30 minutes and at ambient temperature.
The reaction mixture is subsequently heated for 4 hours to 70° C. and left to stand overnight.
After precipitation in water and the conventional treatments 52.6 grams of a mixture of the two products are obtained.
By crystallisation of the residue in hexane the 2-[(4-methoxy)phenoxy]-2-phenyl-N,N-dimethyl-n-butylamine (22) is isolated.
Weight=10.5 grams, yield=13%, m.p.=55°-57° C.
Hydrochloride: m.p.=163°-164° C.
From the mother liquors of this first product 1-[(4-methoxy)phenoxymethyl]-1-phenyl-N,N-dimethyl-n-propylamine (21) is isolated in the form of DL camphosulphonate. Weight=40.2 grams, yield=28%, m.p.=154°-155° C.
As the following toxicological and pharmacological tests demonstrate, the amino-ether oxides according to the invention possess local and spasmolytic anesthetic properties. Certain products also have a considerable analgesic activity. These various properties make the products according to the invention valuable pharmaceutical agents.
The acute toxicity of the products of the invention was determined on groups of 20 Swiss OF1 mice weighing 22 to 24 grams by intravenous route. These toxicities are expressed as the LD50 corresponding to the dose at which a 50% mortality of the treated animals is noted after 8 days of observation. The limits of confidence of these values were determined by the method of Litchfield and Wilcoxon (J. Pharmacol. Exp. Ther. 1949, pages 96 to 99) and are given in table III.
The local anaesthetic activity on contact is determined on the cornea of the rabbit according to a method derived from the technique of Regnier (Regnier J. R. Salle P. Bull. Soc. Pharmacol. 1926 33, 91).
Male albino rabbits weighing 2 to 3 kg are used in groups of 5. The product solution to be tested is injected in a volume of 0.2 ml into the conjunctival sac. The cornea is then stimulated by means of a hair 3, 6, 10, 15, 20, 25, 45 and 60 minutes after injection.
The average number of stimulations is calculated for each group and this number is compared with that obtained with a lidocaine hydrochloride solution of equal concentration. The local anaesthetic activity is thus expressed in relation to this reference product.
The activity of the products is thus compared with that of a known anaesthetic: lidocaine (table IV).
Isolated organs
The spasmolytic activity of the products was studied in vitro with regard to two distinct agonists, namely:
1. barium chloride whose contracting effects was demonstrated on the rat duodenum;
2. nicotine whose contracting effect was demonstrated on the guinea-pig ileum.
The organ fragments were kept alive in a tank containing a solution of Tyrode (37° C., pH 7.2, oxygenated by the mixture O2 /CO2, 95%/5%).
The isotonic contractions were recorded graphically on a physiograph by means of a transducer. For each substance the effect-dose straight line is determined according to semi-logarithmic coordinates and the EC50 is calculated graphically, that is the concentration of the substance necessary to reduce by 50% the amplitude of the contraction of convulsant agent. The values obtained are compared with those of spasmolytic agents selected as reference and are determined under the same experimental conditions, namely:
papaverine hydrochloride for the convulsant effect of barium chloride;
hexamethonium dibromide for the convulsant effect of nicotine (table V).
The analgesic activity of the products was studied on male Sprague-Dawley rats in groups of 15 by a method derived from that of Randall and Selito (Arch. Int. Pharmacodyn. 1957 (III) page 409). This method consists in causing a painful inflammation in the paw of the rat by injecting 0.1 ml of a 20% brewer's yeast solution, then applying a pressure to the inflammation and determining the value of the pressure at which a painful reaction of the animal appears.
The activity of the products was studied after 1 hour of administration by oral route at the rate of one dose of 100 mg/kg in comparison with untreated animals. In this test aspirin was chosen as reference substance.
The analgesic effect of the products is expressed by the percentage increase of the pressure endured by the treated animals in relation to that endured by the untreated animals.
The results of the analgesic activity of the product tested are expressed in relation to the activity of aspirin administered by oral route at a dose of 100 mg/kg. The results obtained are collated in table VI.
The compounds of the invention show anti-spasmodic, anaesthetic and analgesic activities useful in therapy.
These compounds are useful for all the spasmodic states of the smooth musculature and for the painful syndromes which are associated therewith.
By way of non-limiting example they can be used in:
gastroenterology, in oesophagitis, gastroduodenal ulcer, gastritis, biliary dyskinesia, hepatic colic, spasmodic colitis, gastrointestinal malfunction as well as for the treatment of nausea and vomiting;
urology, in nephritic colics and pain of the urinary passages;
gynaecology, in spasmodic dysmenorrhea and dynamic dystocia (spasms of the cervix);
in vascular disturbances, to alleviate the cerebral and peripheral ischemia associated with arterial spasms.
In these indications the unit therapeutic dose of the products is between 10 and 200 mg, preferably between 20 and 100 mg of active ingredient for 100 to 2000 mg of excipient.
The daily therapeutic dose is between 10 mg and 2 grams, preferably between 50 and 500 mg.
The active ingredients of the present invention are administered by the various routes applicable to humans and in the therapeutic forms compatible with these routes.
These various forms prepared from active substances (bases or salts) are produced by methods known per se.
Mention may be made as examples of these preparations of tablets, coated pills, capsules, ovules, powders, solutions, suspensions, ointments, gels and suppositories. The "sustained release" forms of these preparations can likewise be used.
To illustrate in a non-limiting way the production of these preparations, the production of tablets and of injectable isotonic solutions containing the active ingredients of the invention are given below.
______________________________________                                    
(1)   Tablets            mg                                               
      Active substance according to                                       
      Example 2          50.0                                             
      Lactose            26.5                                             
      Mannitol           55.0                                             
      Medicinal white sugar                                               
                         11.0                                             
      Polyethylene glycol 6000                                            
                         5.0                                              
      Magnesium stearate 2.0                                              
      Gelatine           0.5                                              
      Corn starch        50.0                                             
      Total              200.0                                            
______________________________________
The gelatine and medicinal white sugar are dissolved separately in water. The two solutions are mixed and the polyethylene glycol 6000 is added thereto.
The lactose and mannitol are mixed intimately and then the active substance of Example 2, corn starch and the solution obtained above are added in order.
The paste is dried, granulated and screened, while adding the magnesium stearate and corn starch.
The obtained product is homogenised and compressed at the rate of 200.0 mg per tablet.
______________________________________                                    
(2)   Injectable isotonic solution                                        
                           mg                                             
      Active substance according to                                       
      Example 3            10                                             
      Sodium chloride       9                                             
      Distilled water (sufficient to make)                                
                           1 ml                                           
______________________________________
The isotonic solution is distributed in ampoules of suitable volume which, after sealing, are sterilised by thermal means known per se or the solution is sterilised by filtration and distributed in ampoules which are then sealed. All these operations are effected under sterile atmosphere.
In the latter case, it is preferable to add to the formula described 1% of benzyl alcohol as bacteriostatic agent, that is 10 mg of this alcohol per ml of solution.
              TABLE III                                                   
______________________________________                                    
LD.sub.50 of the products of the invention in mice                        
by intravenous route                                                      
                                  Limits of                               
Example                           confidence                              
No.     Salt          LD .sub.50 mg/kg.sup.-1                             
                                  mg/kg.sup.-                             
______________________________________                                    
1       DL camphosulph                                                    
                      30          29-32                                   
2       H. maleate    42          41-43                                   
3       H. maleate    41.4        38.5-44.5                               
4       H. maleate    26.8        25.1-28.6                               
5       hydrochloride 37          28-49                                   
6       H. maleate    48.6        44.6-55.3                               
7       hydrocholride 37          36-39                                   
8       hydrochloride 52.3        48.2-55.8                               
9       hydrochloride 39          37-41                                   
10      hydrochloride 43          41-45                                   
11      hydrochloride 46.7        42.2-51.6                               
12      hydrochloride 34          30-39                                   
13      H. maleate    48.4        45.0-52.2                               
15      DL camphosulph                                                    
                      160.0       143.8-178.0                             
17      hydrochloride 51.6        45.8-58.4                               
18      H. maleate    27.3        25.2-29.6                               
19      hydrochloride 30.7        25-37                                   
21      DL camphosulph                                                    
                      140.4       131.4-150.0                             
22      hydrochloride 59.6        55.5-64.0                               
lidocaine                                                                 
        hydrochloride 31.5                                                
______________________________________
The LD50 of papaverine hydrochloride and of hexamethonium bromide are respectively 33.1 and 21.0 mg/kg.
              TABLE IV                                                    
______________________________________                                    
Results of the local anaesthetic activity of                              
the products of the invention                                             
(activity in 1% solution compared with that of lidocaine                  
hydrochloride at an identical concentration)                              
                        Effect compared                                   
Example No.                                                               
           Salt         with lidocaine                                    
______________________________________                                    
1          DL camphosulph                                                 
                        1.6                                               
2          H. maleate   2.2                                               
3          H. maleate   1.4                                               
7          hydrochloride                                                  
                        1.1                                               
9          hydrochloride                                                  
                        0.7                                               
11         hydrochloride                                                  
                        1.0                                               
13         H. maleate   1.1                                               
19         hydrochloride                                                  
                        0.95                                              
12         hydrochloride                                                  
                        1.7                                               
21         DL camphosulph                                                 
                        0.45                                              
______________________________________
The other compounds of the invention show a comparable local activity.
              TABLE V                                                     
______________________________________                                    
Spasmolytic activity of the products of the                               
invention compared with                                                   
(a) papaverine hydrochloride in the test with BaCl.sub.2                  
(b) hexamethonium dibromide in the nicotine test.                         
                        Rat       Guinea-pig                              
                        duodenum  ileum                                   
                        Ba Cl.sub.2                                       
                                  nicotine                                
Example No.                                                               
         Salt           50 mg/l   1 mg/l                                  
______________________________________                                    
1        DL camphosulph 2.7       0.9                                     
2        H.maleate      5.4       1.2                                     
3        H.maleate      0.9       3.4                                     
5        hydrochloride  0.5       2.2                                     
7        "              1.7       1.0                                     
9        "              0.4       1.4                                     
10       "              0.4       1.7                                     
11       "              1.9       2.6                                     
12       "              1.2       2.3                                     
21       DL. camphosulph                                                  
                        1.7       1.7                                     
papaverine                                                                
         hydrochloride  1         --                                      
hexametho-                                                                
         dibromide      --        1                                       
nium                                                                      
______________________________________
The other compounds according to the invention have comparable spasmolytic properties.
              TABLE VI                                                    
______________________________________                                    
Results of the analgesic activity of the products of the                  
invention at a dose of 100 mg/kg by oral route in relation                
to aspirin                                                                
Example No.   Salt         Activities                                     
______________________________________                                    
 1            DL. camphosulph                                             
                           1                                              
 5            hydrochloride                                               
                           2.5                                            
10            hydrochloride                                               
                           1.8                                            
11            hydrochloride                                               
                           2.3                                            
aspirin                    1                                              
______________________________________
Index of Activity of the Products of the Invention
An index of activity relating to the products of the invention in relation to the reference substance used in each test was calculated for the local anaesthesia test and the spasmolysis tests in vitro.
This index I was calculated with regard to both the activity and the relative toxicity of the products of the invention in relation to the reference substances, namely lidocain hydrochloride, papaverine hydrochloride and hexamethonium dibromide. To eliminate the differences due to the molecular weights of the products, the calculations were made in mmoles. ##EQU1##
For the products of the invention the results are collated in the following table VII.
              TABLE VII                                                   
______________________________________                                    
Relative indices of activity of the products of the                       
invention in relation to:                                                 
lidocaine hydrochloride for local anaesthetic                             
 activity;                                                                
 papaverine hydrochloride for spasmolytic activity                        
 in vitro on the rat duodenum;                                            
 hexamethonium dibromide for spasmolytic activity in                      
 vitro on the guinea-pig ileum.                                           
Ex-    local anaethesia/                                                  
                    spasmolytic  spasmolytic                              
ample  lidocaine hydro-                                                   
                    index/papaverine                                      
                                 index/hexameth-                          
No.    chloride index                                                     
                    hydrochloride                                         
                                 onium dibromide                          
______________________________________                                    
1      1.52         2.45         1.29                                     
2      2.95         6.90         2.42                                     
3      1.85         1.125        6.69                                     
5      --           0.56         3.85                                     
7      1.30         1.89         1.75                                     
9       0.875       0.475        2.62                                     
10     --           0.525        3.50                                     
11     1.49         2.69         5.76                                     
12     1.84         1.24         4.09                                     
13     1.71         --           --                                       
19     0.92         --           --                                       
21     2.00         7.28         11.33                                    
______________________________________
It is noted that the relative index of activity of the products of the invention in local anaesthesia is at least comparable to that of lidocaine hydrochloride and is in many cases 1.5 to 3 times higher.
The spasmolytic activity in vitro as compared with papaverine shows that, apart from the products of Examples 5, 9 and 10, the indices are up to seven times higher than those of the reference for the products of Examples 2 and 21.
Compared with hexamethonium dibromide, the indices are all nearly 7 to 11 times higher in respect of this reference for the products of Examples 3 and 21.
References known by Applicant are U.S. Pat. No. 2,649,445 and French patent 5012 M.
In U.S. patent R1, m and q cannot have the same meanings as in the present invention.
In the french patent the carbon atom which bears R1 is not tetrasubstituted.

Claims (9)

What we claim is:
1. Amino-ether oxide of formula: ##STR18## in which: R1 is lower alkyl,
R2 and R3 which are the same or different are hydrogen or lower alkyl,
R4 is a phenyl or phenoxy nucleus optionally monosubstituted to trisubstituted by substituents which are the same or different, halogen or lower alkoxy,
R5 is a phenyl radical optionally monosubstituted to trisubstituted by substituents which are the same or different, halogen, lower alkyl, lower alkoxy or nitro, a pyridyl radical or a lower alkyl radical,
n is equal to zero, 1 or 2,
m and q are equal to 0 or 1,
p is an integer from 0 to 9 with the proviso that n, m and p are not all equal to 0 when q is equal to 1, and its acid addition salts.
2. Amino-ether oxides according to claim 1, wherein the halogen atoms which appear therein are chlorine atoms or bromine atoms.
3. Amino-ether oxides according to claim 1 or 2, wherein R5 is methyl.
4. Amino-ether oxide according to claim 1, which is 1-[(3,4-dimethoxy)benzyloxymethyl]-1-phenyl-N,N-dimethyl-n-propylamine.
5. Amino-ether oxide according to claim 1, which of 1-[(3,4,5-trimethoxy)benzyloxy]-1-phenyl-N,N-dimethyl-n-propylamine.
6. Amino-ether oxide according to claim 1, which is 1-benzyloxymethyl-1-phenyl-N,N-dimethyl-n-propylamine.
7. Amino-ether oxide according to claim 1, which is 1-[(3,4,5-trimethoxy)benzyloxymethyl]-1-phenyl-N-methyl-n-propylamine.
8. Amino-ether oxide according to claim 1, which is 1-[(4-chloro)benzyloxymethyl]-1-methyl-1-[(4-methoxy)-phenyl]-N,N-dimethylamine.
9. Pharmaceutical agent having antispasmodic, anesthetic and analgesic activities, comprising a physiologically acceptable excipient and an effective amount of an amino-ether oxide of formula: ##STR19## in which: R1 is lower alkyl,
R2 and R3 which are the same or different are hydrogen or lower alkyl,
R4 is a phenyl or phenoxy nucleus optionally monosubstituted to trisubstituted by substituents which are the same or different, halogen or lower alkoxy,
R5 is a phenyl radical optionally monosubstituted to trisubstituted by substituents which are the same or different, halogen, lower alkyl, lower alkoxy or nitro, a pyridyl radical or a lower alkyl radical,
n is equal to zero, 1 or 2,
m and q are equal to 0 or 1,
p is an integer from 0 to 9 with the proviso that n, m and p are not all equal to 0 when q is equal to 1 and its pharmaceutically acceptable acid addition salts.
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4692469A (en) * 1982-09-07 1987-09-08 Ciba-Geigy Corporation Propylamine derivatives
US4824868A (en) * 1982-09-07 1989-04-25 Ciba-Geigy Corporation Propylamine derivatives useful for the treatment of dementia
US5126375A (en) * 1983-04-18 1992-06-30 Glaxo Group Ltd. Phenethanolamine derivatives
US5245080A (en) * 1989-02-20 1993-09-14 Jouveinal Sa (+)-1-[(3,4,5-trimethoxy)-benzyloxymethyl]-1-phenyl-N,N-dimethyl-N-propylamine, process for preparing it and its therapeutical use
US5266599A (en) * 1989-02-20 1993-11-30 Jouveinal S.A. Use of (+)-1-[(3,4,5-trimethoxy)-benzyloxymethyl]-1-phenyl-N,N-dimethyl-n-propylamine to increase gastric discharge in a subject
US20040010035A1 (en) * 2002-07-15 2004-01-15 Ciociola Arthur A. Gastrointestinal compositions
US20040013741A1 (en) * 2002-07-15 2004-01-22 Meisel Gerard M. Gastrointestinal compositions
WO2004006901A1 (en) * 2002-07-10 2004-01-22 Warner-Lambert Company Llc Gastrointestinal compositions comprising gaba derivatives
US20050136127A1 (en) * 2002-07-10 2005-06-23 Meisel Gerard M. Gastrointestinal compositions
US20060293393A1 (en) * 2005-06-28 2006-12-28 Catholic Healthcare West (D/B/A/ St. Joseph's Hospital And Medical Center) Iptakalim hydrochloride for decreasing nicotine use
US20070185127A1 (en) * 2004-04-14 2007-08-09 Astrazeneca Ab 2-(Arylalkoxy)-1-phenylethylamine derivatives as nk1 antagonist and serotonin reuptake inhibitors
US20070275905A1 (en) * 2005-05-27 2007-11-29 Antibe Therapeutics Inc. Salts of trimebutine and n-desmethyl trimebutine

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0102929B1 (en) * 1982-09-07 1987-07-01 Ciba-Geigy Ag Propylamine derivatives, process for their preparation, pharmaceutical compositions containing these compounds, and their therapeutical use
FR2643369B1 (en) * 1989-02-20 1991-07-05 Jouveinal Sa LA (+) 1 - ((3,4,5-TRIMETHOXY) BENZYLOXYMETHYL) -1-PHENYL-N, N-DIMETHYL-N-PROPYLAMINE, ITS PREPARATION PROCESS AND ITS APPLICATION IN THERAPEUTICS
CA2110513A1 (en) * 1991-07-05 1993-01-21 Christopher J. Swain Aromatic compounds, pharmaceutical compositions containing them and their use in therapy
US5472978A (en) * 1991-07-05 1995-12-05 Merck Sharp & Dohme Ltd. Aromatic compounds, pharmaceutical compositions containing them and their use in therapy
US5495047A (en) * 1991-07-10 1996-02-27 Merck, Sharp & Dohme (Ltd.) Fused tricyclic compounds, pharmaceutical compositions containing them and their use in therapy
JPH06509090A (en) * 1991-07-10 1994-10-13 メルク　シヤープ　エンド　ドーム　リミテツド Aromatic compounds, compositions containing them and their use in therapy
US5328927A (en) * 1992-03-03 1994-07-12 Merck Sharpe & Dohme, Ltd. Hetercyclic compounds, processes for their preparation and pharmaceutical compositions containing them
GB9211193D0 (en) * 1992-05-27 1992-07-08 Merck Sharp & Dohme Therapeutic agents
WO1994003429A1 (en) * 1992-07-31 1994-02-17 Merck Sharp & Dohme Limited Substituted amines as tachykinin receptor antagonists
JP3870419B2 (en) * 1994-08-22 2007-01-17 三菱ウェルファーマ株式会社 Benzene compounds and their use as pharmaceuticals
US5948820A (en) * 1994-08-22 1999-09-07 Yoshitomi Pharmaceutical Industries, Ltd. Benzene compound and pharmaceutical use thereof
PL211954B1 (en) 2002-01-11 2012-07-31 Sankyo Co Amino alcohol derivative or phosphonic acid derivative and medicinal composition containing these
AU2005215320B2 (en) 2004-02-24 2008-04-17 Sankyo Company, Limited Amino alcohol compound

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3106564A (en) * 1958-08-21 1963-10-08 Parke Davis & Co 1-(2-phenoxy-2-phenylethyl) pyrrolidine
US4194009A (en) * 1974-01-10 1980-03-18 Eli Lilly And Company Aryloxyphenylpropylamines for obtaining a psychotropic effect
US4207343A (en) * 1978-06-22 1980-06-10 Eli Lilly And Company 1-Phenyl-3-(substituted phenoxy)propylamines

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2649445A (en) * 1948-02-28 1953-08-18 Bristol Lab Chloracetic acid ester of diphenyl ethanols
GB1119835A (en) * 1964-07-20 1968-07-17 Analyses Et De Rech S Biolog M Process for the preparation of basic ethers

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3106564A (en) * 1958-08-21 1963-10-08 Parke Davis & Co 1-(2-phenoxy-2-phenylethyl) pyrrolidine
US4194009A (en) * 1974-01-10 1980-03-18 Eli Lilly And Company Aryloxyphenylpropylamines for obtaining a psychotropic effect
US4207343A (en) * 1978-06-22 1980-06-10 Eli Lilly And Company 1-Phenyl-3-(substituted phenoxy)propylamines

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4692469A (en) * 1982-09-07 1987-09-08 Ciba-Geigy Corporation Propylamine derivatives
US4824868A (en) * 1982-09-07 1989-04-25 Ciba-Geigy Corporation Propylamine derivatives useful for the treatment of dementia
US5126375A (en) * 1983-04-18 1992-06-30 Glaxo Group Ltd. Phenethanolamine derivatives
US5245080A (en) * 1989-02-20 1993-09-14 Jouveinal Sa (+)-1-[(3,4,5-trimethoxy)-benzyloxymethyl]-1-phenyl-N,N-dimethyl-N-propylamine, process for preparing it and its therapeutical use
US5266599A (en) * 1989-02-20 1993-11-30 Jouveinal S.A. Use of (+)-1-[(3,4,5-trimethoxy)-benzyloxymethyl]-1-phenyl-N,N-dimethyl-n-propylamine to increase gastric discharge in a subject
US20050136127A1 (en) * 2002-07-10 2005-06-23 Meisel Gerard M. Gastrointestinal compositions
WO2004006901A1 (en) * 2002-07-10 2004-01-22 Warner-Lambert Company Llc Gastrointestinal compositions comprising gaba derivatives
US20040013741A1 (en) * 2002-07-15 2004-01-22 Meisel Gerard M. Gastrointestinal compositions
US20040010035A1 (en) * 2002-07-15 2004-01-15 Ciociola Arthur A. Gastrointestinal compositions
US6986901B2 (en) * 2002-07-15 2006-01-17 Warner-Lambert Company Llc Gastrointestinal compositions
US20070185127A1 (en) * 2004-04-14 2007-08-09 Astrazeneca Ab 2-(Arylalkoxy)-1-phenylethylamine derivatives as nk1 antagonist and serotonin reuptake inhibitors
US7368448B2 (en) 2004-04-14 2008-05-06 Astrazeneca Ab 2-(arylalkoxy)-1-phenylethylamine derivatives as NK1 antagonist and serotonin reuptake inhibitors
US20080234282A1 (en) * 2004-04-14 2008-09-25 Astrazeneca Ab 2-(Arylalkoxy)-1-Phenylethylamine Derivatives As NK1 Antagonist And Serotonin Reuptake Inhibitors
US20070275905A1 (en) * 2005-05-27 2007-11-29 Antibe Therapeutics Inc. Salts of trimebutine and n-desmethyl trimebutine
US7666907B2 (en) 2005-05-27 2010-02-23 Antibe Therapeutics Inc. Salts of trimebutine and N-desmethyl trimebutine
US20060293393A1 (en) * 2005-06-28 2006-12-28 Catholic Healthcare West (D/B/A/ St. Joseph's Hospital And Medical Center) Iptakalim hydrochloride for decreasing nicotine use
US7879913B2 (en) 2005-06-28 2011-02-01 Catholic Healthcare West Iptakalim hydrochloride for decreasing nicotine use
US20110144188A1 (en) * 2006-06-06 2011-06-16 Antibe Therapeutics Inc. Salts of trimebutine and n-desmethyl trimebutine

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IT1136190B (en) 1986-08-27
DE3026201A1 (en) 1981-02-26
FR2460919A1 (en) 1981-01-30
NL8003601A (en) 1981-01-13
DE3026201C2 (en) 1990-11-08
GB2054588B (en) 1983-06-29
ES8103020A1 (en) 1981-02-16
JPS5615250A (en) 1981-02-14
US4301163B1 (en) 1990-01-23
GB2054588A (en) 1981-02-18
NL190237C (en) 1993-12-16
CH644348A5 (en) 1984-07-31
JPS6253504B2 (en) 1987-11-10
CA1148547A (en) 1983-06-21
IT8012595A0 (en) 1980-07-11
ES493092A0 (en) 1981-02-16
NL190237B (en) 1993-07-16
FR2460919B1 (en) 1983-11-10
BE884212A (en) 1981-01-08

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